Phase II study of cytarabine in men with docetaxel‐refractory, castration‐resistant prostate cancer with evaluation of TMPRSS2‐ERG and SPINK1 as serum biomarkers

• Published in: BJU international 2012-09, Vol.110 (6), p.840-845
• Main Authors: Dhani, Neesha C., Emmenegger, Urban, Adams, Laurie, Jongstra, Jan, Tannock, Ian F., Sridhar, Srikala S., Knox, Jennifer J., Day, John R., Groskopf, Jack, Joshua, Anthony M.
• Format: Article
• Language: English
• Subjects: Aged; Antimetabolites, Antineoplastic - therapeutic use; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Biomarkers; Biomarkers - blood; Carrier Proteins - genetics; Castration; cytarabine; Cytarabine - therapeutic use; Drug Resistance, Neoplasm; Gynecology. Andrology. Obstetrics; Humans; Male; Male genital diseases; Medical sciences; Men; Middle Aged; Nephrology. Urinary tract diseases; Prostate cancer; Prostatic Neoplasms - blood; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; RNA, Messenger - blood; Serine Endopeptidases - genetics; SPINK1; Taxoids - therapeutic use; TMPRSS2‐ERG; Trans-Activators - genetics; Transcriptional Regulator ERG; Trypsin Inhibitor, Kazal Pancreatic; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland
• ISSN: 1464-4096; 1464-410X
• DOI: 10.1111/j.1464-410X.2011.10922.x

Study Type – Therapy (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? To date, there has been limited impetus to examine the use of cytarabine in prostate cancer. We presented preliminary laboratory data to suggest its utility in the castration refractory prostate cancer (CRPC) population which, combined with a previous case report, suggested it may have hitherto unrecognized utility in this setting. Embedded in this study was peripheral blood sampling for TMPRSS2‐ERG and SPINK1, two genes that are believed to define prostate cancer genotypes, to assess their utility as biomarkers This study suggests that at the delivered doses, cytarabine has limited efficacy and significant myelotoxicity suggesting, it does not have a role in the treatment of docetaxel‐refractory CRPC. The presence of serum TMPRSS2‐ERG and SPINK1 mRNA biomarkers recovered from blood suggest that their analysis is worthy of further study. OBJECTIVES •  To run a phase II clinical trial of cytarabine in men with docetaxel‐refractory, castration‐resistant prostate cancer (CRPC), based on evidence that cytarabine might be effective in men with abnormalities of ERG oncogenes. •  To measure mRNA levels of prostate cancer‐related genes in blood as biomarkers. PATIENTS AND METHODS •  Ten of a planned maximum of 30 men received i.v. cytarabine at doses of 0.25–1g/m2 at 21‐day intervals. The primary endpoint was prostate‐specific antigen (PSA) response. •  Archival tumour samples were assessed by fluorescence in‐situ hybridization for TMPRSS2:ERG translocation, and by immunohistochemistry for serine peptidase inhibitor Kazal type 1 (SPINK1). •  Blood was processed for mRNA quantification of TMPRSS2:ERG (exon1:exon4), SPINK1 and PSA. RESULTS •  A PSA response was not observed in any patient. The trial was stopped at the end of stage 1 of a modified Flemming design. •  The median number of cycles administered was 3. Grade 3–4 haematological toxicity was common. Five patients were subsequently excluded from the study for toxicity, and five for disease progression. •  Analysis of whole blood mRNA for T1:E4 translocation in TMPRSS2:ERG was consistent with that in the tumour in 8/9 evaluable cases (one was concordantly positive, seven were concordantly negative), SPINK1 results were concordant in 9/10 cases (two were concordantly positive, seven were concordantly negative [P= 0.047 for the predictive value]). •  There was no correlation between PSA or SPINK protein